One strategy in developing new cancer therapeutics having better toxicity profiles compared with current cytotoxic drugs is to utilize molecularly-targeted therapeutics that selectively target cancer cells versus normal cells and can be used in minimal doses to reduce side effects. Death receptor ligands held initial promise in answering this need because they trigger programmed cell death in their target cancer cells. Two of the best-studied death receptor ligands, Fas ligand and tumor necrosis factor-alpha (TNF-α), have proven to be too toxic for systemic use as anticancer agents in their native forms. However, another death receptor ligand, tumor necrosis factor-α-related apoptosis-inducing ligand, known as TRAIL, and its receptors, has renewed interest in this area of cancer research. Active TRAIL receptors, TR1 (DR4) and TR2 (DR5) are often more highly expressed on cancer cells versus normal cells. Inactive TRAIL “decoy” receptors TR3 (DcR1) and TR4 (DcR2) are sometimes more prevalent on the surface of normal cells. Both DR4 and DR5 transduce death signaling, leading to apoptosis upon binding to TRAIL, whereas DcR1 and DcR2 lack intact intracellular death domain and therefore cannot signal apoptosis despite binding to TRAIL. Instead, DcR1 or DcR2 protects cells from TRAIL-induced apoptosis by competing with DR4 and DR5 for binding to TRAIL. Interestingly, the expression of DcR1 and DcR2 is either downregulated or lost in many types of cancer cells or tissues while DR4 and DR5 expression are maintained in cancer cells or tissues. This inversely related expression pattern for TRAIL receptors may be partly responsible for the selectivity of TRAIL ligand for tumor cells over normal cells, and its ability to preferentially cause apoptotic cell death in cancer cells, may contribute to a more favorable safety profile.
TRAIL ligand exists in two forms: as a type II membrane protein expressed on the surface of certain lymphoid cells, and as a cleaved, soluble protein that is detectable in serum. While the biological roles of TRAIL ligand in vivo have not been fully elucidated, recombinant soluble TRAIL causes apoptosis in sensitive tumor cells but not normal cells. Therefore, various TRAIL ligand formulations have been investigated for their therapeutic efficacy as well as possible toxicity in mice, cynomolgus monkeys, and humans. In response to the poor serum stability of recombinant TRAIL in vivo and in an attempt to create more targeted therapeutics with fewer side effects, humanized agonistic monoclonal TRAIL antibodies, such as mapatumumab and lexatumumab, were developed that have either TR1 (i.e., DR4) or TR2 (i.e., DR5) specificity. Phase I and II clinical trials have been carried out using these antibodies as single agents in patients having solid tumors such as colorectal cancer, non-small cell lung cancer, and non-Hodgkin's lymphomas. The useful in vivo half-lives, good tolerability, low toxicity, and efficacy in promoting stable disease in certain patient groups observed for agonistic monoclonal antibodies to TR1 and TR2 have provided a basis for the expectation that TRAIL-targeted therapies may have broad clinical applicability in the treatment of cancer.
While TRAIL has been reported to successfully target certain tumor cells which are resistant to traditional chemotherapies or radiation, TRAIL resistance has also been widely documented. Indeed, many cancer cells are quite resistant to TRAIL as a single agent. There is an unmet need for the development of sensitizers of the cancer cells to TRAIL, especially those that act in a synergistic manner.